RC4: PROJECT SUMMARY / ABSTRACT The HIV epidemic has transitioned from a rapidly fatal condition to a chronic manageable infection. Persons living with HIV (PLWH) suffer an early onset of geriatric chronic diseases such as cardiovascular disease, emphysema, cancers, and frailty. Often PLWH have multiple chronic conditions. Accelerated aging and frailty best describe the health of PLWH. The origins of these health disparities are multifactorial but include social, environmental, and economic challenges, and unhealthy behaviors including substance use. Alcohol use disorders (AUDs), in particular, are highly prevalent in PLWH, interrupt the HIV care continuum, and contribute to the pathogenesis of many comorbidities associated with HIV infection. In the preceding cycle of LSUHSC-New Orleans Comprehensive Alcohol-HIV/AIDS Research Center (CARC), we confirmed that lifetime estimates of alcohol use in PLWH positively correlate with phenotypic frailty and biological age in cross-sectional analyses of participants in the CARC?s New Orleans Alcohol Use in HIV (NOAH) longitudinal study. Similarly, we found that alcohol use correlates with T-cell activation, senescence and immune exhaustion. These findings support the importance of AUDs as a determinant of accelerated aging in PLWH and are the premise for the studies proposed in the continuation of this research component Our primary hypothesis is that alcohol use disorder in PLWH increases CD8+ T-cell activation and proliferation and reduces activation-induced cell death, leading to the accumulation of senescent cells. We further hypothesize that long-term alcohol exposure results in cellular and tissue senescence leading to clinical aging. We contend that alcohol increases cellular proliferation and decreases apoptosis leading to more T-cell and tissue senescence. Senescent cells display a highly proinflammatory ?senescence associated secretory phenotype? (SASP), which is thought to mediate tissue dysfunction to cause organ dysfunction and frailty. The overall objective of this proposal is to determine the role of alcohol use in mediating immune, tissue, and organismal aging. Our hypotheses will be tested in bidirectional translational studies in PLWH and HIV-negative participants, and in the chronic binge alcohol (CBA) simian immunodeficiency virus (SIV) non-human primate (NHP) model. Our experimental approach permits testing the impact of alcohol and HIV/SIV in cross-sectional and longitudinal analyses. The Specific Aims of our proposed studies are: Specific Aim 1: To test the hypothesis that alcohol use and HIV-infection increase T-cell senescence by increasing proliferation and decreasing apoptosis; and Specific Aim 2: To test the hypothesis that alcohol use and HIV-infection increase tissue senescence and SASP leading to organ dysfunction and frailty. The expected outcome from this research is validation of our conceptual model connecting alcohol use and precocious biological aging in PLWH. The long- term goal of our research program is to mitigate multimorbidity and frailty due to alcohol use in PLWH.